LincRNA调控miRNA活性影响卵巢浆液性囊腺癌发生的二级结构基础

Ovarian serous cystadenocarcinoma (OSC) is one kind of malignant epithelial ovarian cancer commonly in women, with complicated pathogenesis mechanism. The results of current studies indicated that the abnormal of miRNA activity always cause OSC. Our preliminary data show that the sequences of screened higher expressed lincRNAs based on OSC microarray dataset have many miRNA binding sites, and lincRNA has more conserved secondary structure than its sequence. Therefore we hypothesized that the biogenesis of OSC is affected by lincRNA regulating miRNA activity on the basis of specified secondary structure. In this project, we will utilize information theoretical method to analyze the pathway of lincRNA-miRNA-mRNA in OSC after screening based on microarray dataset; We will study the features of lincRNA global and local secondary structure, and find the structure motif in regulating miRNA activity; we will also investigate how single nucleotide polymorphisms (SNPs) change the lincRNA secondary structure and thus affect the miRNA activity; In the end, we will simulate the dynamic conformational change of lincRNA in regulating miRNA activity using molecular dynamic simulation method. The results gained from the proposed studies will elucidate the molecular mechanism of OSC biogenesis, and provide the scientific clues for preventing and treating OSC.

卵巢浆液性囊腺癌（OSC）为女性多发恶性卵巢上皮癌，发病机理甚为复杂。国内外研究表明miRNA活性异常可导致OSC发生。项目前期针对OSC芯片数据，筛查出OSC相关高表达lincRNA序列上存在诸多miRNA结合位点，且lincRNA二级结构比其序列更为保守。据此推测：lincRNA以特定二级结构调控miRNA活性从而影响OSC的发生发展。因此本项目拟首先筛查OSC相关lincRNA，miRNA及其靶基因；分析lincRNA二级结构的整体与局部特征，发现结构motif，并分析其在调控miRNA活性中的作用，构建lincRNA:miRNA互作模型；研究SNP引起lincRNA二级结构改变对miRNA活性调控作用的影响；通过分子动力学模拟研究lincRNA二级结构动态构像变化对其功能的影响。研究结果有助于阐明OSC发生的分子机理，为OSC的预防及治疗提供有价值的科学线索。

本项目利用TCGA数据库以及收集卵巢浆液性囊腺癌患者组织样本的测序数据展开相关分析研究。针对高通量测序数据的转录本组装还存在装配质量不佳，起始或终止密码子的丢失等问题，我们提出了一种新的lncRNA识别工具lncScore；针对现有方法基于整体表达相关性对lncRNA-miRNA-mRNA竞争性三元组进行筛选，受样本集影响较大，且仅能筛选miRNA中心型候选三元组等问题，我们提出了一种新的lncRNA竞争性三元组识别工具 – LncMiM；基于TCGA数据库中的卵巢癌高通量测序数据，我们分析了lncRNA与含IRES元件mRNA间的相互作用，筛选出110个与含IRES元件mRNA表达相关的lncRNA，并对其潜在功能进行了预测。通过分析非编码RNA中的IRES元件的一级结构、二级结构特征以及与蛋白质相互作用概率等特征，建立了新的IRES元件识别工具IRESfinder。研究结果有助于阐明卵巢浆液性囊腺癌发生的分子机理，为其预防及治疗提供有价值的科学线索和帮助。